SIRT3 regulates cellular iron metabolism and cancer growth by repressing iron regulatory protein 1.
SIRT3 regulates cellular iron metabolism and cancer growth by repressing iron regulatory protein 1.
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DOI：
10.1038/onc.2014.124
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发表时间：
2015-04-16
期刊：
影响因子：
8
通讯作者：
Haigis MC
中科院分区：
文献类型：
--
作者：
Jeong SM;Lee J;Finley LW;Schmidt PJ;Fleming MD;Haigis MC
铁代谢对于许多细胞过程包括氧转运、呼吸和DNA合成是必不可少的，并且许多癌细胞表现出铁代谢的失调。铁调节蛋白（IRP）通过与靶mRNA的铁响应元件（IREs）结合来调控铁相关基因的表达，从而维持细胞内铁稳态。在这里，我们报告线粒体SIRT 3通过调节IRP 1活性来调节细胞铁代谢。SIRT3的缺失增加了活性氧的产生，导致IRP1与IRES结合的增加。因此，IRP1靶基因，如转铁蛋白受体（TfR1），一种对铁吸收和细胞增殖至关重要的膜相关糖蛋白，由SIRT3控制。重要的是，SIRT3缺乏导致细胞铁稳态的缺陷。SIRT3无效细胞含有高水平的铁，并失去铁依赖性TfR1调节。此外，SIRT3敲除小鼠在胰腺中表现出更高水平的铁和TfR1表达。我们发现，铁摄取和TfR1表达的调节有助于SIRT3的肿瘤抑制活性。事实上，在人胰腺癌中SIRT3表达与TfR1表达负相关。SIRT3过表达通过抑制IRP1降低TfR1表达并抑制胰腺癌细胞的增殖。我们的数据揭示了SIRT3通过IRP1调节在细胞铁代谢中的新作用，并表明SIRT3部分通过调节细胞铁代谢发挥肿瘤抑制剂的作用。
Iron metabolism is essential for many cellular processes including oxygen transport, respiration and DNA synthesis, and many cancer cells exhibit dysregulation in iron metabolism. Maintenance of cellular iron homeostasis is regulated by iron regulatory proteins (IRPs), which control the expression of iron-related genes by binding iron-responsive elements (IREs) of target mRNAs. Here, we report that mitochondrial SIRT3 regulates cellular iron metabolism by modulating IRP1 activity. SIRT3 loss increases reactive oxygen species production, leading to elevated IRP1 binding to IREs. As a consequence, IRP1 target genes, such as the transferrin receptor (TfR1), a membrane-associated glycoprotein critical for iron uptake and cell proliferation, are controlled by SIRT3. Importantly, SIRT3 deficiency results in a defect in cellular iron homeostasis. SIRT3 null cells contain high levels of iron and lose iron-dependent TfR1 regulation. Moreover, SIRT3 null mice exhibit higher levels of iron and TfR1 expression in the pancreas. We found that the regulation of iron uptake and TfR1 expression contribute to the tumor suppressive activity of SIRT3. Indeed, SIRT3 expression is negatively correlated with TfR1 expression in human pancreatic cancers. SIRT3 overexpression decreases TfR1 expression by inhibiting IRP1 and represses proliferation in pancreatic cancer cells. Our data uncover a novel role of SIRT3 in cellular iron metabolism through IRP1 regulation, and suggest that SIRT3 functions as a tumor suppressor, in part, by modulating cellular iron metabolism.